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Neoplasia & Cell Death
Revision
Objectives• Terminology of Cell change• Apoptosis vs Necrosis• Neoplasia
– Benign– Malignant
• Tumour classification• Intraepithelial neoplasia• Tumour grading & staging
• Tumour invasion & metastasis• Tumour pathogenesis
– Oncogenes– Tumour suppressor genes
• Cellular mutation– Germline– Somatic
• Population-based screening• Adenocarcinoma sequence• Clinical complications of
tumours• Personalised cancer
management
Cell Change - Atrophy
http://commons.wikimedia.org/wiki/File:Non-neoplastic_changes.svg
Decrease in cell size• development (thymus)• disuse (skeletal muscle)
Cell Change - Hypertrophy
http://commons.wikimedia.org/wiki/File:Non-neoplastic_changes.svg
Increase in cell size [intracellular protein]
• physiological (exercise)• pathophysiological (hypertension)
Cell Change - Hyperplasia
http://commons.wikimedia.org/wiki/File:Non-neoplastic_changes.svg
Increase in number of cells• compensatory (bone marrow)• hormonal (uterus)• pathophysiological (endometriosis)
Cell Change - Metaplasia
http://commons.wikimedia.org/wiki/File:Non-neoplastic_changes.svg
Replacement of one well differentiated cell type by another
• response to irritants (smoking)
Cell Change - Dysplasia
http://commons.wikimedia.org/wiki/File:Non-neoplastic_changes.svg
Abnormal changes in cellular shape, size or organisation
• atypical hyperplasia (pre-cancerous)
ApoptosisProgrammed death of individual cells
• Usually physiological stimuli (development)• Controlled process mediated by cellular signals
Associated with• No inflammation or secondary tissue damage• Integrity of cellular structures retained• Cell death pathway activated (ATP-dependent)
Long-term • Generally no consequences – part of cell cycle• Example – embryological development
http://quizlet.com/13850708/cell-injury-adaptation-and-death-flash-cards/
Necrosis Premature destruction of cell groups
• Pathophysiological stimuli (injury/disease)• Process mediated by extracellular factors
Associated with• Inflammation + secondary tissue damage• Swelling & disintegration of cellular structures• Abnormal pathway (non-ATP dependent)
Longterm•Inflammation and decreasing blood supply result in tissue death (gangrene) → death• Example – cerebral/ myocardial infarction
http://quizlet.com/13850708/cell-injury-adaptation-and-death-flash-cards/
Define Neoplasia
• Lesion due to– Tissue growth: new + abnormal + autonomous– Persists after initiating stimulus has been removed
‘A lesion resulting from new and abnormal tissue growth which persists independent of it’s initiating stimulus’
Caused by carcinogens• chemicals• viruses• radiation• hormones• bacteria, fungi & parasites
Types of Neoplasia - Benign
Slow-growing• have a low mitotic rate of division
Often well circumscribed• no invasion of surrounding lymph/tissue• no metastasis to other areas
Resemble cell of origin• rarely necrotic• rarely ulcerate
http://medical-dictionary.thefreedictionary.com/tumor
Longterm• pressure on adjacent tissues• obstruction of ducts/ hollow organs• produce hormones• can be pre-malignant (causes anxiety)
Types of Neoplasia - Malignant
Fast-growing• have a high mitotic rate of division
Poorly defined, irregular, infiltrative borders• invasion of surrounding lymph/tissue• can metastasise to other areas
Variable resemblance to cell of origin• commonly necrotic• commonly ulcerate
http://medical-dictionary.thefreedictionary.com/tumor
Tumour Classification• Based on ‘behaviour’ of the tumour e.g. Benign or malignant presentation
OR
• Based on histogenetic origin– Degree of histological resemblance between cell of origin & tumour cell– Allows for tumour grading
CELL OF ORIGIN BENIGN MALIGNANT
Epithelial Papilloma or Adenoma Carcinoma
Connective tissue -oma Sarcoma
Lymphoid - Lymphoma
Haemopoietic - Leukaemia
Intraepithelial Neoplasia • Potentially premalignant dysplasia
– Abnormal growth and transformation of cells– Confined to the epithelium (in situ)– May superficially penetrate accessory organ structures
http://www.nature.com/nrc/journal/v7/n7/fig_tab/nrc2154_F1.html
Tumour Grading & Staging• Utilised for malignant tumours only – have generally good prognostic value
• Staging – Histopathological & clinical tumour assessment – Measures level of tumour spread throughout body– Example: TNM (Tumour, Node, Metastasis) staging
• Grading– Histopathological tumour assessment– Measures degree of histological differentiation– Example: Gleason grading for prostate cancer
Objectives• Terminology of Cell change• Apoptosis vs Necrosis• Neoplasia
– Benign– Malignant
• Tumour classification• Intraepithelial neoplasia• Tumour grading & staging
• Tumour invasion & metastasis• Tumour pathogenesis
– Oncogenes– Tumour suppressor genes
• Cellular mutation– Germline– Somatic
• Population-based screening• Adenocarcinoma sequence• Clinical complications of
tumours• Personalised cancer
management
Phase 2a
Lucy Faulkner Phase 3a
The Peer Teaching Society is not liable for false or misleading information…
• Oncogenes and tumour suppressor genes • Germ line and somatic mutations• Population based screening• Adenoma-carcinoma sequence in the colorectum• Complications of tumours • The future of personalized medicine
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Aims
• A proto-oncogene is a normal gene that can become an oncogene due to mutations or increased expression.
• An oncogene is a genes that drives the neoplastic behavior of cells
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Onco- and tumour suppressor genes
• A tumour suppressor gene is a gene which inhibits the transformation of a cell into a neoplastic state
The Peer Teaching Society is not liable for false or misleading information…
Onco- and tumour suppressor genes
• Mutations in proto-oncogenes and tumour suppressor genes leads to neoplasia
• Mutations in proto-oncogenes leads to excessive cell division or prevent apoptosis from occurring
• Mutation in tumour suppressor genes prevents DNA repair leading to mutations, leads to excessive cellular proliferation or prevents apoptosis from occurring
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Onco- and tumour suppressor genes
• Germline mutation: A mutation occurring in gametes.
• They are passed on to offspring and are present every cell in the offspring.
• Somatic mutation: acquired mutations occurring in any of the cells of the body except the germ cells.
• They cannot be passed on to offspring.The Peer Teaching Society is not liable for false or misleading information…
Germline and somatic mutations
• Screening: checking apparently healthy people with no symptoms to identify those who may be at increased risk of a disease or condition
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Population based screening
Why screen for cancer?•Early detection gives a better prognosis•Tumours are found at a curable stage and before they have metastasized
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Population based screening
Problems with screening
•Lead time bias•Early abnormalities detected by screening may not have progressed to malignant neoplasms•Some people are reluctant to be screened
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Population based screening
• Cancer screening tests in the UK: breast cancer, cervical cancer, bowel cancer screening
• Screening also offered to those at high risk (BRCA1, BRCA2, FAP)
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Population based screening
The Peer Teaching Society is not liable for false or misleading information…
Adenoma-carcinoma sequence • Stepwise progression from benign to
malignant neoplasms due to an accumulation of mutations
• The mutations occurring in this sequence are well defined in colorectal cancer
The Peer Teaching Society is not liable for false or misleading information…
Adenoma-carcinoma sequence
Normal Mjepithelium Mj
Small Mjadenoma Mj
Large Mjadenoma Mj
Invasive Mjadenocarcinoma Mj Metastases Mj
APC mutation MjMCC Mj mutation Mj
5q deletion Mjc-myc Mj Mj
activation Mj' Mjsusceptibilty Mj Mjgene' 8q24 Mj k-ras Mj mutation Mj
Chromosome Mj17q, 18q Mjdeletion Mj
Tp53 mutation Mj nm23 mutation Mj
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Adenoma-carcinoma sequence
• Why do cancers cause a problem?• Local effects • Metastases• Paraneoplastic/metabolic effects
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Complication of tumours
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Complication of tumours
Complications Mjof tumours Mj
Local effects MjMetabolic effects Mj
Metastases Mj
Local invasion Mj
Ulceration Mj
Destruction of adjacent structures Mj
Compression MjTumour specific Mj
Non-specific Mj
Gastointestinal Mj blood loss MjAnaemia Mj
Airway obstruction Mj
Bowel obstruction Mj
Cachexia Mj
Dysphagia Mj
Lethargy Mj
Malaise Mj
Finger clubbing Mj
Tumour produces a hormone Mj
Hypertrophic Mjosteoarthropathy Mj
Thyrotoxicosis Mj
Cushing's Mj
Hyperparathyroidism Mj
Infection Mj
Hypercalcaemia Mj of malignancy Mj
SIADH Mj
Lambert-Eaton Mjmyasthenic Mj syndrome Mj
Carcinoid Mj syndrome Mj
Haematongenous Mj spread Mj
Lymphatic spread Mj
Transcoelomic Mj spread Mj
Implantation Mj
Complications Mjof tumours Mj
• Cancer treatments targeted to the genetics of a patients cancer
• May enable more effective treatments of cancer in the future
• Examples: Trastuzumab, Imatinib
The Peer Teaching Society is not liable for false or misleading information…
Personalized medicine
• Give some examples of a tumour suppressor gene?
• P53, RB1, APC, BRCA1, BRCA2, MSH2, MLH1• Give some examples of inherited cancer
syndromes• Multiple endocrine neoplasia syndrome (MENS),
Xeroderma pigmentosum, familial polyposis coli, von Hippel-Lindau syndrome, Li-Fraumeni syndrome, retinoblastoma, familial breast cancer
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Questions
• Name the hormone/substance produced which causes the following paraneoplastic syndromes:Cushing’s, SIADH, Carcinoid syndrome, Lambert-Eaton myasthenic syndrome, hypoglycaemia
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Questions
• Name the hormone/substance produced which causes the following paraneoplastic syndromes:
• Cushing’s, SIADH, Carcinoid syndrome, Lambert-Eaton myasthenic syndrome, hypoglycaemia
• Cushings: ACTH and ACTH-like substance• SIADH: ADH• Carcinoid syndrome: serotonin• Lambert-Eaton myasthenic syndrome: antibodies against
presynaptic voltage-gated calcium channels• Hypoglycaemia: Insulin or insulin-like substance[7] or "big" IGF-II
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Questions
• A patient has previously been diagnosed with a squamous cell lung cancer. They come to you complaining of polydipsia, polyuria, constipation and muscle weakness. On questioning they admit to being depressed recently– Which paraneoplastic syndrome are they likely to have
developed?– What substance produced by the tumour causes this
effect?– What change would you see on ECG if this is not
corrected?The Peer Teaching Society is not liable for false or misleading information…
Questions
– What paraneoplastic syndrome are they likely to have developed?
– Hypercalcaemia of malignancy– Which substance produced by the tumour causes
this effect?– Parathyroid hormone like peptide– What change would you see on ECG?– Short QT interval
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Questions
• General and Systematic Pathology
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References/ useful resources
• NHS cancer screening website: http://www.cancerscreening.nhs.uk/index.html
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Questions
The Peer Teaching Society is not liable for false or misleading information…
Questions
The Peer Teaching Society is not liable for false or misleading information…
Thank you